TFE3 – Perivascular Epithelioid Cell Neoplasm

Perivascular epithelioid cell neoplasms (PEComas) are rare mesenchymal tumors defined by co-expression of melanocytic and myogenic markers. A subset harbors chromosomal rearrangements of the X-linked TFE3 transcription factor gene, distinguishing them from TSC1/2-mutant PEComas. TFE3-rearranged PEComas display characteristic epithelioid nested or alveolar morphology and underexpression of smooth muscle markers, and they follow a clinical course that can range from indolent to aggressive.

Several independent case reports have confirmed TFE3 fusions in primary PEComas of the bladder and uterus. A benign bladder PEComa in a 27-year-old male exhibited an SFPQ-TFE3 fusion detected by RT-PCR and confirmed by FISH (1 proband) (PMID:29531006). In contrast, a malignant bladder PEComa in a 55-year-old woman recapitulated epithelioid morphology with FISH-confirmed TFE3 rearrangement and showed rapid metastatic progression (PMID:23797724). Additional genitourinary tract PEComas, including uterine tumors, similarly demonstrated TFE3 rearrangements and variable histologic aggressiveness (PMID:32576448; PMID:37575749).

A comprehensive cohort study of 38 PEComas revealed nine TFE3-rearranged cases (23%) identified by RNA sequencing and FISH, with three SFPQ-TFE3 and one DVL2-TFE3 fusion, among others (PMID:25651471). These TFE3-positive tumors were equally distributed between soft tissue and visceral sites, and none harbored coexisting TSC2 mutations, indicating a distinct molecular subgroup. The mutual exclusivity with TSC1/2 loss-of-function alterations supports alternative oncogenic pathways in PEComa pathogenesis.

Morphologically, TFE3-rearranged PEComas exhibit predominant epithelioid cell nests or alveolar architecture around delicate vasculature and often demonstrate reduced smooth muscle actin expression. Molecular validation via break-apart FISH and fusion transcript detection confirms the driver role of TFE3 fusions. Although no dedicated in vivo PEComa models exist, the distinctive histopathologic and genetic features provide robust diagnostic criteria.

Clinically, recognition of TFE3 rearrangements refines diagnostic accuracy, influences risk stratification, and may inform therapeutic decisions, such as de-escalation of mTOR inhibitors that target TSC-mutant PEComas. Given the variable clinical behavior, molecular subtyping facilitates prognostic assessment and may guide enrollment in trials of targeted agents against MiT/TFE family oncogenic drivers.

In summary, TFE3 rearrangements define a genetically and morphologically distinct subset of PEComas with strong evidence of oncogenic driver status. Integration of FISH or RNA-seq for TFE3 fusions into diagnostic workflows is recommended to optimize clinical management. Key Take-home: TFE3-rearranged PEComas constitute a distinct molecular entity warranting tailored diagnostic and therapeutic approaches.

References

• Annals of clinical and laboratory science • 2018 • TFE3-Expressing Epithelioid Rich Perivascular Epithelioid Cell Neoplasm (PEComa) of the Bladder with Unusual Benign Course. PMID:29531006
• The American journal of surgical pathology • 2013 • Malignant perivascular epithelioid cell neoplasm (PEComa) of the urinary bladder with TFE3 gene rearrangement: clinicopathologic, immunohistochemical, and molecular features. PMID:23797724
• Clinical genitourinary cancer • 2020 • TFE3 Gene Rearrangement in Perivascular Epithelioid Cell Neoplasm (PEComa) of the Genitourinary Tract. PMID:32576448
• Cureus • 2023 • Malignant Perivascular Epithelioid Cell Tumor of the Uterus. PMID:37575749
• The American journal of surgical pathology • 2015 • Dichotomy of Genetic Abnormalities in PEComas With Therapeutic Implications. PMID:25651471

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